Liver toxicity precludes development of pembrolizumab plus pazopanib immunotherapy for patients with advanced renal cell carcinoma (RCC), according to findings from a phase I/II clinical safety and efficacy study presented (abstract 4506) at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.
“The combination is not feasible due to hepatotoxicity,” reported lead study author Simon Chowdhury, MBBS, MRCP, PhD, of the Sarah Cannon Research Institute in London.
When a sequential therapy regimen was explored, hepatotoxicity was not limiting but other severe adverse events emerged, “requiring multiple dose modifications and making the combination not feasible,” Chowdhury said. “Pazopanib is not recommended in combination with pembrolizumab.”
Pazopanib is a standard first-line therapy for patients with advanced RCC. Combination therapies under investigation include immune checkpoint inhibitors with targeted agents. The research team evaluated the safety and efficacy of pazopanib plus pembrolizumab, a humanized monoclonal immunoglobulin immunotherapy that targets programmed death 1 receptors.
After a dose-escalation phase, 20 patients were enrolled in expansion cohorts to determine maximum tolerated dose and recommended phase II dose. Patients were administered pazopanib (600 mg or 800 mg once daily) with pembrolizumab (2 mg/kg every 2 weeks and then every 3 weeks). The patients experienced significant, dose-limiting liver toxicity, but the combination also exhibited early signs of antitumor activity.
Grade 3/4 adverse events occurred in 90% of these two dose-finding cohorts, leading to permanent discontinuation in 50% and 80% of them, respectively, following dose interruptions or reductions. One of the 20 patients died on treatment.
The research team therefore sought to assess whether or not tolerability could be improved in a third cohort of patients administered a sequential therapy regimen of pazopanib run-in (800 mg daily for 9 weeks) followed by pazopanib (800 mg daily) and pembrolizumab (2 mg/kg every 3 weeks) alone or in combination. Eligibility criteria included adult patients with locally advanced or metastatic RCC with predominantly clear-cell histology, no prior systemic therapy, ECOG performance status scores of 0 or 1, and adequate organ function.
A total of 21 patients were enrolled in the third cohort, of whom 17 completed the pazopanib run-in. Six patients received pazopanib plus pembrolizumab, 4 received pembrolizumab monotherapy, and 7 received pazopanib monotherapy.
Four of the five patients receiving combination treatment following the pazopanib run-in experienced grade 3/4 adverse events leading to dose interruptions, and in one case, permanent discontinuation. Unlike the first two cohorts, among whom increased alanine transaminase (ALT) and aspartate transaminase (AST) were frequent (> 50%), none of the five patients in the run-in combination cohort experienced increased ALT or AST, nor did they experience hypertension, which had occurred in 20% of both of the earlier dose-finding cohorts. However, patients in the third cohort experienced increased amylase and lipase, diarrhea, confusion, perforation of the large intestine, nausea, pneumonitis, and pulmonary embolism.
None of the patients in the third cohort experienced complete responses, and only one experienced partial response; three patients had stable disease.